We studied mechanisms by which T cells recognize antigens presented by major histocompatibility complex (MHC)-encoded molecules on cell surfaces, and the applications to the design of synthetic vaccines for AIDS and cancer. We developed synthetic vaccines for HIV using broadly reactive HIV helper apitopes combined with CTL and neutralizing antibody epitopes, and showed the importance of covalent linkage of helper and CTL epitopes for induction of CTL, never before demonstrated. We found an adjuvant allowing induction of CTL, TH1 help, and neutralizing antibodies with the same immunication, and just commenced a human phase I immunotherapy trial with these vaccine constructs. We found in murine studies that peptide vaccines for HIV can be made more potent or broadly effective by selective introduction of mutations that improve binding to MHC to T-cell receptors ("epitope enhancement"). To apply this approach to human vaccines we studied the binding of HIV envelope peptides to human HLA molecules, and raised HIV peptide-specific human CTL from blood of an uninfected individual. We made second generation vaccine constructs to show the feasibility of enhancing immunogenicity in mice. We developed a murine tumor model expressing HIV gp160 to test vaccine efficacy, and showed protection against HIV-envelope-expressing tumor challenge. We showed suppression of CTL activity and viral clearance in an animal model, and identified CD3+4-8- cells suppressing the CTL response. We studied the mechanism by which free peptide inhibits CTL, and developed a method to induce high affinity CTL. We developed a new vaccine construct using a portion of anthrax toxin to introduce recombinant protein into the class I mHC processing pathway. We found HIV-peptide- reactive T cells in 75% of seronegative health-care workers exposed to HIV+ blood. We identified several CTL epitopes in proteins of the hepatitis C virus, that causes liver cancer, and demonstrated the predictive value of HLA-transgenic mice in identifying these peitopes. We showed a correlation between IL-2 response to human papillomavirus peptides and stage of cervical neoplastic disease. We developed peptide cancer vaccines inducing CTL immunity to mutant p53 expressed in cancer cells, and also induced murine CTL against fusion proteins from chromosomal translocations in pediatric tumors. Sixteen cancer patients have been treated in a phase I/II clinical trial of mutant p53 or ras peptide vaccine and results are pending. We found that the spacing of hydrophobic pockets in the MHC groove enforces an amphipathic periodicity on the peptides bound.